Recent studies demonstrate that IgD was present in the ancestor of all jawed vertebrates and arose together with IgM at the time of the emergence of the adaptive immune system, approximately 500 million years ago. While IgM remains stable over evolutionary time, IgD shows greater structural plasticity and can be predominantly expressed as a transmembrane or secretory molecule in a species-specific manner.
IgM and IgD are the first antibody isotypes expressed during B cell ontogeny. Bone marrow B cell precursors acquire surface IgM after assembling heavy (H) and light (L) chain variable region exons from prototypic variable (V), diversity (D) and joining (J) gene segments through an antigen-independent process mediated by recombination activating gene (RAG)-1 and RAG-2 proteins. After leaving the bone marrow to colonize secondary lymphoid organs, 13 cells acquire surface IgD of the same specificity as surface IgM through alternative splicing of a pre-messenger RNA comprising VDJ and both heavy chain constant μ (Cμ) and Cδ exons (Maki et al., Cell 24: 353-365, 1981). The significance of dual IgM and IgD expression remains unclear, because either isotype largely compensates for the loss of the other (Nitschke et al., Proc. Natl. Acad. Sci. USA 90: 1887-1891, 1993; Roes et al., J. Exp. Med. 177: 45-55, 1993; Lutz et al., Nature 393: 797-801, 1998).
After encountering antigen in secondary lymphoid organs, mature B cells transcriptionally down-regulate surface IgD (Monroe et al., Eur. J. Immunol. 13: 208-213, 1983) and thereafter undergo somatic hypermutation (SHM) and class switch DNA recombination (CSR), two Ig gene-diversifying processes that require the DNA-editing enzyme activation-induced cytidine deaminase (AID) (Muramatsu et al., Cell 102: 553-563, 2000). SHM introduces point mutations into VHDJH and VLJL exons, thereby providing the structural correlate for selection of high-affinity Ig variants by antigen (Odegard et al., Nat. Rev. Immunol. 6: 573-583, 2006), whereas CSR substitutes the Cμ gene with Cγ, Cα or Cε, thereby generating secondary IgG, IgA and IgE isotypes with the same antigen binding specificity as IgM but additional effector functions (Chaudhuri et al., Nat. Rev. Immunol. 4: 541-552, 2004). Ultimately, antigen-experienced B cells generate antibody-secreting plasma cells and memory B cells (McHeyzer-Williams et al., Curr. Opin. Immunol. 11: 172-179, 1999). These latter cells form new plasma cells upon exposure to previously encountered antigens. In general, plasma cell-derived IgG, IgA and IgE antibodies facilitate the elimination of invading pathogens by activating powerful Fe receptors that enhance the phagocytic, cytotoxic and pro-inflammatory functions of various innate immune cells, including granulocytes (Stavnezer et al., Adv. Immunol. 61: 79-146, 1996).
Instead of switching from IgM to IgG, IgA or IgE, some B cells switch to IgD (Arpin et al., J. Exp. Med. 187: 1169-1178, 1998) The resulting IgD+IgM− plasma cells release highly mutated mono- and polyreactive IgD antibodies mostly containing λ IgL chains in the blood as well as respiratory, salivary, lacrimal and mammary secretions (Rowe et al., J. Exp. Med. 121: 171-199, 1965; Preudthomme et al., Mol. Immunol. 37: 871-887, 2000; Plebani et al., Clin. Exp. Immunol. 53: 689-696, 1983; Liu et al., Immunity 4: 603-613, 1996; Brandtzaeg et al., Immunol. Rev. 171: 45-87, 1999; Koelsch et al., J. Clin. Invest. 117: 1558-1565, 2007). IgD-deficient mice have fewer B cells, delayed affinity maturation, and weaker production of IgG1 and IgE, two isotypes dependent on the cytokine interleukin-4 (IL-4) (Nitschke et al., Proc. Natl. Acad. Sci. USA 90: 1887-1891, 1993; Roes et al., J. Exp. Med. 177: 45-55, 1993) Conversely, mice injected with anti-IgD antibodies produce more IgG1 and IgE and show robust IL-4 production by T cells and basophils (Conrad et al., J. Exp. Med. 171: 1497-1508, 1990; Seder et al., Proc. Natl. Acad. Sci. USA, 88: 2835-2839, 1991; Yoshimoto et al., Science 270: 1845-1847, 1995). These latter are a small granulocytic subset that triggers T and B cell responses by releasing IL-4 upon recognizing antigen via pre-bound IgE and IgG (Gauchat et al., Nature 365: 340-343, 1993).